PROJECT SUMMARY Mutations in the X-linked gene encoding cyclin-dependent kinase-like 5 (CDKL5) cause the childhood epileptic encephalopathy known as CDKL5 disorder. The disease is characterized by a heterogeneous array of clinical symptoms including early-onset seizures, marked hypotonia, autistic-like features, and severe neurodevelopmental impairment. To confirm the genetic causality of CDKL5 disorder, we generated the first Cdkl5 knockout (KO) mouse and found that mice lacking CDKL5 mirror several hallmark symptoms of the human disease, including autistic-like behaviors, impaired motor control, disrupted auditory-evoked event- related potentials, and poor learning and memory. Interestingly, Cdkl5 KO mice also exhibit perturbed dendritic spine density, morphology, and LTP. These early findings suggest an important role for CDKL5 in neuronal synapse function. However, CDKL5?s specific role in this context, particularly post-development, remains unknown. Given these synaptic phenotypes caused by CDKL5 loss, and my recent preliminary data using a novel adult KO model of CDKL5, I hypothesize that CDKL5 expression is required in adulthood to maintain proper synaptic homeostasis, circuit communication, and behavioral output. Thus, the goal of this proposal is to elucidate the adulthood requirement of CDKL5 in synaptic function by 1) determining the sufficiency of CDKL5 in restoring loss-of-function circuit and behavioral deficits at adulthood and 2) determining the extent to which CDKL5 modulates synaptic density and morphology in vivo. My ultimate goal is to determine a novel role for CDKL5 in the maintenance of adult neural function. These studies will provide essential preclinical information regarding disease reversibility, and pave the way for the future development of more targeted therapeutics for CDKL5 disorder patients.